Related Experiment Videos
The glucocorticoid receptor and STAT6 physically and functionally interact in T-lymphocytes
1INSERM U461, Faculté de Pharmacie Paris XI, 5 rue J.-B. Clément, 92296 Cedex, Châtenay-Malabry, France.
Abstract:
In lymphocytes, glucocorticoids (GC)- and interleukin-4-signaling pathways are known to interact, as evidenced by inhibition of IL-4-mediated proliferation by dexamethasone or suppression of GC-induced apoptosis by IL-4. In this study, we characterized the molecular basis for this reciprocal interference. We report that, in murine CTLL-2 cells, IL-4 inhibits GC-induced MMTV (mouse mammary tumor virus) promoter transactivation, and that GC suppress IL-4-induced transactivation of a STAT6 (signal transducers and activators of transcription 6)-responsive promoter without affecting IL-4-stimulated STAT6 DNA-binding. Moreover, we evidenced a physical association between GC receptor and STAT6, which proved to be functionally relevant, since STAT6 overexpression increased the IL-4 inhibitory effect on GC-induced MMTV transactivation.
Insights
Interleukin-4 (IL-4) and glucocorticoid (GC) signaling pathways interact in lymphocytes. This study reveals IL-4 inhibits GC-induced MMTV promoter activity, while GC suppresses IL-4-induced STAT6 promoter activity, mediated by a physical association between GC receptor and STAT6.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- Glucocorticoids (GC) and Interleukin-4 (IL-4) signaling pathways exhibit known interactions in lymphocytes.
- These interactions include inhibition of IL-4-mediated proliferation by dexamethasone and suppression of GC-induced apoptosis by IL-4.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the reciprocal interference between GC and IL-4 signaling pathways.
- To investigate the functional consequences of the physical association between the GC receptor and STAT6.
Main Methods:
- Utilized murine CTLL-2 cells to study signaling pathway interactions.
- Assessed transactivation of the mouse mammary tumor virus (MMTV) promoter by GC.
- Examined transactivation of a STAT6-responsive promoter by IL-4.
- Investigated STAT6 DNA-binding activity.
- Performed co-immunoprecipitation to detect physical association between GC receptor and STAT6.
Main Results:
- IL-4 was found to inhibit GC-induced MMTV promoter transactivation in CTLL-2 cells.
- GC suppressed IL-4-induced transactivation of a STAT6-responsive promoter.
- GC did not affect IL-4-stimulated STAT6 DNA-binding.
- A physical association between the GC receptor and STAT6 was demonstrated.
- STAT6 overexpression enhanced the IL-4-mediated inhibition of GC-induced MMTV transactivation.
Conclusions:
- The molecular basis for reciprocal interference between IL-4 and GC signaling involves direct interaction between the GC receptor and STAT6.
- This interaction modulates the transcriptional activity of both signaling pathways.
- Findings provide insights into the complex interplay of immune and stress response signaling in lymphocytes.